After balloon angioplasty, a metal tubular scaffold structure called a stent may be permanently implanted to physically hold open the repaired coronary artery. Unfortunately, up to 30% of such procedures result in reclosure (restenosis) of the artery within six months to one year. One solution to the problem is to provide acute local, postoperative radiation treatment of the site using a catheter tipped with iridium-192 radioisotope. In this method the iridium-192 tipped catheter is placed at the arterial site for thirty to forty minutes after stent deployment and then retracted. This type of acute high dose treatment using gamma radiation has been found to substantially reduce the rate of subsequent restenosis, as noted in Wiedermann, J. G. et al., "Intracoronary Irradiation Markedly Reduces Restenosis After Balloon Angioplasty in a Porcine Model," 23 J. Am. Coll. Cardiol., 1491-1498 (May 1994) and Tierstein, P. S. et al., "Catheter-Based Radiotherapy to Inhibit Restenosis After Coronary Stenting," 336 New England Journal of Medicine, 1697-1703 (Jun. 12, 1997).
An alternate method of addressing the restenosis problem is to form the structural material of the stent itself from a radioactive material as described by Fischell R. et al. in U.S. Pat. No. 5,059,166 (the '166 patent) and in U.S. Pat. No. 5,376,617 (the '617 patent). The '166 and '617 patents also describe a method of electroplating a radioactive material on the structural material of the stent. Each of these methods has certain drawbacks. Placement of radioactive material within the structural material of the stent can deteriorate the physical properties of the structural material, such as stiffness, and can present fabrication difficulties with respect to radiation exposure of workers during the manufacturing process. The electroplating process, on the other hand, may result in poor adhesion of the radioactive material, which could delaminate during insertion.
Moreover, an additional requirement for any clinically useful-stent is that it should have good x-ray visibility. A fairly thick (ten to fifteen micron) radiopaque coating of a high density, high atomic number metal such as gold, platinum, or iridium may be coated on the structural material of the stent in order to achieve visibility in an x-ray. Placing the radioactivity within the structural material, as taught by the '166 and '617 patents, may preclude coating the stent with a radiopaque metal. A high density metal that is approximately fifteen microns thick will absorb and reduce the kinetic energy of beta rays emitted from the structural material under the coating.
Further, the '166 and the '617 patents mention the possibility of plating the radioisotope Au.sup.198 on the structural material of the stent. It is highly unlikely that plating of Au.sup.198 would make the stent radiopaque because the coating would be less than a few angstroms thick. As noted by Fischell et al. in the article "Low-Dose .beta.-Particle Emission From `Stent` Wire results in Complete, Localized Inhibition of Smooth Muscle Cell Proliferation", 90 Circulation 2956-2963 (1994) (the Fischell article), radioactivity on the order of one microcurie is preferred for a coronary stent. Using an Au.sup.198 plating solution containing typically 18 Ci/g of dissolved gold (following a two-week cooldown period after activation in a nuclear reactor), a total activity of 1 .mu.Ci would require a total coating mass of 0.055 .mu.g, which, when distributed over the surface of an entire coronary stent, would have a thickness of about one monolayer of gold. Such a thin layer would not add contrast in an x-ray picture of the stent. Moreover, Au.sup.198 is not a pure beta ray emitter, it has numerous gamma rays, which may give a radioactive dose to the entire body of a patient instead of a localized dose to a target area in the coronary artery. Au.sup.198 also has a half-life (2.7 days) that is too short to be practical for an intra-arterial coronary stent.
Another method mentioned in the Fischell article and further investigated by Laird, J. R. et al., in "Inhibition of Neointimal Proliferation with Low-Dose Irradiation from .beta.-Particle Emitting Stent," 90 Circulation 529 (1996) (the Laird article), is to impregnate titanium stents with up to thirty atomic percent of stable phosphorous and subsequently activate the entire stent in a nuclear reactor to form the radioisotope P.sup.31 within the titanium structural material. One of the disadvantages of the Laird method is that the massive quantity (30 at. %) of phosphorous required to make even 0.15 microcurie of P.sup.31 may severely alter the structural strength of the stent itself.
The references discussed above do not suggest any way to adapt the radioactive stent embodiments of the '166 and '617 patents and also make the stent radiopaque. In the preferred embodiment of the '166 and '617 patents, the structural material is doped with an activatable element and then made radioactive in a nuclear reactor. The resulting radioactive stent would be extremely difficult to subsequently sputter coat with a thick (up to 15 micron) coating of gold. The radiation safety challenges for the factory workers would be considerable and would therefore render the technique impractical for mass production purposes. In addition, the sputter cleaning process, which would generally be necessary to achieve good adhesion, could emit radioactive structural material and contaminate the inside walls of the coating apparatus.
If the radiopaque metal is coated first and the coated stent is then placed in a nuclear reactor, the coating could activate gamma emitting isotopes to curie levels and render the stent undesirable for human use. For example, the thermal neutron reaction cross section for a gold radiopaque coating is 198 barns, which could activate a 15 .mu.m thick gold coating to 10 tens of curies in a one week of irradiation.
Similar problems arise if the radioisotope is plated on the structural material of the stent, which is the alternate embodiment mentioned in the '166 and '617 patents. For this alternate embodiment, the sputter cleaning step prior to the radiopaque material coating could remove the radioactive material and distribute it throughout the inside walls of the coating apparatus. Gold is a very inert metal. As a result, if the gold is coated on the structural material first and then the radioactive material is plated on the gold outer surface, it could be extremely difficult to get the plating to adhere. The preferred radioactive plating of phosphorous-32 generally cannot be plated onto gold. The only radioisotope which can readily plate on gold is Au.sup.198, but, as noted above, Au.sup.198 is a gamma and beta ray emitter with a half-life (2.7 days) that is too short to be of clinical interest.
A method of plating a stent with a high density, radiopaque metal or alloy is disclosed in U.S. Pat. No. 5,607,442 to Fischell et al. (the '442 patent). The '442 patent describes a stent that is plated on its longitudinal wires with a radiopaque metal with a sufficient thickness so that the longitudinal wires will be clearly radiopaque in fluoroscopy. The circumferential wires of the stent are described as being plated with a much lesser thickness than the longitudinal wires so that they will not be distinctly radiopaque. The '442 patent describes the purpose of coating the longitudinal wires as being to assist the cardiologist in determining whether the stent has been fully and uniformly deployed throughout its entire length, thereby obviating the need for use of an intravascular ultrasound catheter. The '442 patent describes the purpose of coating the circumferential wires as being to avoid electrolytic corrosion of the stent by using a single metal outer coating on all stent surfaces, and, when plating with gold, to provide an attractive appearance for the stent. The '442 patent suggests that the circumferential wires should not be radiopaque because, if all the stent wires are radiopaque, such as if the stent is made from tantalum, then the stent may be so radiopaque as to obscure some of the lumen within the implanted stent.
The '442 patent also mentions in passing that the stent could include a radioisotope that is incorporated by ion implantation into the metal of the stent, or could include a radioisotope that is placed on the stent below an anti-thrombogenic coating. The '442 patent appears to indicate that the radioisotope should be ion implanted directly into the structural material of the stent. As noted above, ion implantation of radioactive material within the structural material of the stent can present fabrication difficulties. In addition, the high density radiopaque material plated on the longitudinal wires would absorb and reduce the kinetic energy of beta rays emitted from the structural material under the plating on the longitudinal wires, thereby causing a disparity in the spatial distribution of the beta radiation, which would be more intense longitudinally than circumferentially. Such spatial nonuniformity generally would be less desirable for reducing hyperplasia than a uniform distribution.
Another significant disadvantage of the methods disclosed in the references discussed above is the absence of any technique for assuring that the radiopaque coating sticks to the structural material of the stent. This disadvantage is particularly important when the radiopaque material is gold. In practice, gold plating, such as that disclosed in the '442 patent, cannot be electroplated directly onto stainless steel or nitinol. Moreover, the gold plating described in the '442 patent could be rubbed off during handling by medical personnel as well as during, and subsequent to, placement in a patient's body. Gold flaking could interfere with the deployment of the stent. If, for example, a proportionally substantial amount of the radiopaque gold on a longitudinal wire were to flake off, it could suggest, falsely, to the interventional cardiologist that the stent had not fully expanded. The cardiologist could then decide, reasonably but mistakenly, to inflate a very high pressure balloon within the stent, as disclosed in the '442 patent, in an attempt to correct the deployment of the stent. The stent also could be placed at the wrong position within the artery because the stent's length appeared shorter under fluoroscopy due to flaking off of the gold plating.
These difficulties may be overcome and a stent that is both radiopaque and radioactive may be fabricated using the present invention.